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  Issue 2 (2003)

Dermopharmacy News
7th Annual Meeting of the Society for Dermopharmacy in Bonn on 1st and 2nd April 2003
Innovative Approach for the Treatment and Prevention of Skin Diseases

Report by Thomas Müller-Bohn, Süsel

The 7th Annual Meeting of the GD Gesellschaft für Dermopharmazie took place at the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (Federal Institute for Pharmaceuticals and Medicinal Products) in Bonn on 1 and 2 April 2003 and was visited by more than 200 participants. By selecting this venue, the GD expressed its efforts aiming at good contacts with the authorities relevant for dermopharmaceutic questions. Scientific head of the meeting was GD-member professor Dr. med. h. c. Thomas Ruzicka, director of the dermatological clinic of Heinrich-Heine-University, Düsseldorf. In accordance with the GD's interdisciplinary objective the event presented a diversified program conveying a large variety of subjects in the field of dermopharmacy.

Apart from the scientific main program, a poster exhibition as well as further lectures regarding special topics took place. Thus the GD-department Dermocosmetics organized a workshop under the title "Cleansing and care of skin prone to acne", whereas the department Dermatopharmacology realized a symposium concerning the subject "Innovative dermatics: from molecule to authorization" (vide summary on page 23). The program was complemented by an evening event at the Kunstmuseum Bonn, in the frame of which the first Dermopharmazie-Innovation Prize (DIP) was conferred (vide page 4). An additional highlight was the symposium "Topical immuno modulators: established ones and future indications", initiated by the company Fujisawa Deutschland GmbH concluding the meeting at the Gästehaus Petersberg in Königswinter.

In his opening address relating to the scientific main program, the GD president Dr. Joachim Kresken, Viersen, expressed his thanks to the BfArM for the excellent cooperation in the preparation of the meeting in the new prestigious premises. The program itself virtually covered all sections of dermopharmacy with lectures from the fields dermopharmaceutical chemistry, pharmaceutical technology, bio pharmacy, dermatopharmacology, dermatotherapy and dermocosmetics. It was for the first time supplemented by two midday seminars organized by the companies Galderma and Trommsdorff. Subjects of these seminars were the photodynamic therapy and the application of nail plasters at onychodystrophy.

The 7th Annual Meeting of the GD was opened up by the GD president Dr. Joachim Kresken.

Authorization Obstacles for Dermatics

The main program started with a position paper of a scientist from the BfArM, professor Dr. med. Achim Zesch, dealing with the authorization procedure at the BfArM and the Europäische Arzneimittelbehörde EMEA (European Pharmaceuticals Authority). In the course of the Mutual Recognition Procedure, MRP, the original authorization country acts as commentator for the procedures in the other member countries. A denegation in this authorization procedure is particularly redoubtable as this could jeopardize already effected national authorization retrospectively.

Venue of the 7th Annual Meeting of the GD was the extension of the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (Federal Institute for Pharmaceuticals and Medicinal Products) in Bonn.

In his function of dermatologist Zesch equally went into the special features which have to be considered for the authorization of topical dermatics. The benefit-risk assessment poses in most cases minor problems if the preparation subject to authorization is to be applied on small skin areas only. If however, systemic effects are to be expected for applications on large areas, other presentation forms are often more favorable than preparations for external application.

Professor Dr. med. Achim Zesch, BfArM informed about problems in the authorization of dermatics.

A further question relevant for the authorization is the frequently intrinsic activity of the vehicle. At some preparations for topical application the active substance is to a lesser degree responsible for the effect compared with the effect of the vehicle. However, also such products are authorized if the effectiveness of the preparation has been proven by studies. Vice versa an inappropriate vehicle can also have a contra-productive influence on the therapy effect. In many cases the effectiveness test is difficult to perform for diseases correlating with an increased self-healing rate and pronounced psychosomatic effects.

The demands to fixed combinations for preparations for external applications are very high so that the application for an authorization is often not worth the effort. The equivalence proof for generics is often more demanding for preparations for external application than with other forms of administration: a different vehicle justifies a new product with the necessity of performing clinical studies. An exception are here only the topical glucocorticoids for which the drain-off test has been recognized as procedure for the equivalence analysis.

Molecular Modelling at Topical Glucocorticoids

Professor Dr. Hans-Dieter Höltje, Düsseldorf reported about a project that took place in cooperation with the working group of professor Dr. Monika Schäfer-Korting, Berlin, and is considered to be an example of a successful interaction of pharmaceutico-chemical and pharmacological research. As a result, a molecular model of the glucocorticoid receptor has been produced by means of which reliable statements about the bonding power of pharmaceuticals at the receptors are possible. The molecular modelling supports the search for new pharmaceuticals and contributes to the understanding of known distinctions in the benefit-risk relation of topical glucocorticoids.

The progesterone-receptor served as starting point of the tests. Its crystal structure is known and shows a good homology to the glucocorticoid receptor. With the aid of different calculation methods, a model could be developed at which the physiologic ligand cortisol and several glucocorticoids could be very well adapted into the binding pocket of the receptor.

However, this first model does not explain the bond of all effective substances, in particular major ester groups protrude from the bond area. In reality, this bond region is obviously variable and able to adapt to larger molecules by employment of energy. Thus, also molecules with different volumes and alignment of substituents are able to bind. Dynamic tests simulating the use of warmth were able to amplify the model by this aspect.

The quality of the model is outlined by calculations at which the data for some of the tested substances can be predicted by means of comparisons with the data of the respectively other substances. Nevertheless, not only predictions about the ligands are possible but even a contribution of single amino acids of the receptor to the bonding properties could be determined.

Batches of new insights of dermopharmacy: this could be an interpretation of the work of art in the foyer of the BfArM-building in view of the 7th Annual Meeting of the GD

Nitrogen Oxide as New Therapeutic Principle

The small nitrogen oxide monoxide radical has in recent years been subject to an enormous number of scientific publications. The substance is also formed in the skin in high concentrations at certain conditions. Which physiological background and therapeutic consequences this may have, has been investigated by professor Dr. Victoria Kolb-Bachofen and colleagues at the Institut für Immunbiologie (Institute for Immune Biology) at Heinrich-Heine University Düsseldorf.

The NO-radical is in particular formed in inflammatory situations by an induceable nitrogen monoxide synthesis (iNOS) from the amino acid L-Argninin. Contrary to first presumptions the radical itself does not contribute to the destruction of the tissue but fulfils regulatory functions which are apparently also maintained in tumor cells. Kolb-Bachofen herself was surprised about the test results according to which the NO is non-toxic even in very high concentrations.

The iNOS expression represents a normal response of the human skin to UV-radiation. It develops at healthy persons within one day after radiation and is no longer detectable after three days. The iNOS-expression however fails to appear at first with patients suffering from cutaneous lupus and establishes only with a three-day delay.

Tests at skin biopsies have revealed that the iNOS is neither sufficiently active in psoriasis-lesions. Further, it could be proven that both the induction of the NO synthesis and the exogenously supplied NO via different ways protect from apoptoptic cell death by UVA-radiation. Thus in a first test series based on six healthy test persons, the erythema could be reduced and the skin pigmentation enhanced by application of a NO-containing cream during the UV-radiation.

Liposomal Encapsulation of
Dermatological Active Substances

Encapsulation of dermatological active substances in liposomes was the subject of a lecture by professor Dr. Alfred Fahr from the Institut für Pharmazeutische Technologie (Institute for Pharmazeutical Technology) of Jena University. The crucial factor for the infiltration of the liposomes in deeper skin layers is their formability. An additional driving force is obviously the moisture gradient between skin and ambiance. Liposomal dermatic preparations should therefore not be applied under occlusive conditions.

Surprisingly, Fahr determined in his tests at model systems with excised human skin from plastic surgery that by encapsulation in fluid liposomes not only the penetration of hydrophilic but also the penetration of in particular lipophilic pharmaceuticals can be enhanced. With the example of the hardly water-soluble immuno suppressant Ciclosporin A this has also been shown in an animal model for Alopecia areata: hairless rats which had been topically treated with liposomally encapsulated Ciclosporin A regained a normal fur growth within only a few weeks. Other preparations in which Cyclosporin A had been applied in presence of classical penetration agents as alcohol did however not show any effect at the same test conditions.

A guided tour of the Kunstmuseum Bonn was a welcome variation to the scientific parts of the lectures.

Quality Assurance of Dermatological Prescriptions

Dr. Bernd Fröhlingsdorf, Hilden, explained the requirements as to basic principles and other raw materials used for the preparation of dermatological prescriptions in pharmacies. In Germany approximately 2.000 raw materials for the prescriptions are negotiated - less than half of them are monographed. Due to the market conditions virtually all raw materials are supplied with test certificates so that in pharmacies merely the identity has to be checked. This provision equally concerns the prescription bases which are available in trade as cosmetics or other branded articles.

Anne Kresken was in charge of the conference office as in earlier Annual Meetings of the GD. She was supported by her son Jan Kresken (left).

The quality assurance chain starts with the producer who has to prove an efficient quality assurance system and usually monitors regularly based on his producer authorization according to §13 AMG. It stretches further from packaging firms and wholesalers to the pharmacy which is ultimatively responsible for the quality of the prescription due to § 11 Apothekenbetriebsordnung (Pharmacy Work Rules). Further regulations referring to the quality requirements concern the storage of the raw materials, the packing materials for prescriptions and the prohibition of the preparation and dispensing of questionable pharmaceuticals.

Resorption Tests at the Perfused Cow's Udder

Professor Dr. Manfred Kietzmann, Hannover, presented the isolated perfused cow's udder which had already been developed in 1993 as model for testing of the resorption of substances through the skin. This model allows better predications than mere in-vitro models and excels by its large application area and high perfusion volume. The udders delivered from slaughterhouses are applied within one hour after slaughter and are maximally usable for 24 hours from this point in time.

As example for the usability of this model, Kietzmann presented results from tests for the percutaneous resorption of beta methasone-17,21-dipropionate from different dermatic bases, of estradiol from transdermal therapeutic systems as well as nonyl phenol and bisphenol A as toxicologically revelant substances. In tests with betamethason-17,21-diproprionate it could be shown that the drug from ointment bases with and without additive of propylene glycol has been resorbed to a higher degree as expected than from a dilution, a cream and a gel. After previous impairment of the horny layer barrier with acetone the resorption rates were significantly increased at all tested formulations.

Chemokines as Therapeutic Targets

The afternoon program of the meeting, dealing with innovative approach for the treatment and prevention of skin diseases, was opened by Dr. Bernhard Homey, Düsseldorf. He emphasized the significance of chemokines in dermatology, allergology and oncology in his basic lecture. Chemokines are small proteins similar to cytokins for which 42 human ligands have been found so far. They bind to G-protein-coupled receptors and convey the firm adhesion of leukocytes to endothel cells and their aligned migration.

In dermatology chemokines are particulary suited for the therapy of T-cell-imparted diseases as psoriasis and atopical dermatitis. The skin-specific chemokine CCL27 which is only formed in epidermal keratinocytes imparts by interaction with its specific receptor CCR10 the recruiting of skin-infiltrated T-cells. In inflammated skin the CCL27 is over-exprimized.

Accordingly, antagonists or antibodies against CCL27 would be potential pharmaceuticals directed at inflammations and auto-immuno diseases of the skin. Moreover, efforts are made to identify the chemokine pattern which controls the organ-specific metastazation at different tumor diseases. Chemokines respectively their receptors are thus of interest far beyond dermatology as therapeutic target.

New Therapy Options by TLR-Antagonists

Another innovative target however, is already made use of for therapeutic purposes. Topical immuno stimulators act as agonists of the toll-like receptors (TLR) as explained by professor Dr. med. Wolfram Sterry, Berlin. As concerns physiology, TLR are to recognize microbial structures which are exprimized at the cell surface. In case a TLR is activated, it releases cytokins which then activate the immune system in this field. To date nine different TLR are known in humans that belong to two different subfamilies.

Imiquimod, approved for topical treatment of virus-induced papillomae in genital regions is an antagonist for TLR-7 and TLR-8 present in dendritic cells. The substance activates monocytes and mediates an inflammation by cytokines. The immune system is thus activated similarly to a bacterium and induces the rejection of the cell concerned. It could be shown in several studies that also actinic keratoses and superficial basaliomae respond to a topical therapy with Imiquimod. As the individual TLR are responsible in different tissues for diverse functions, the concept of the TLR-agonists is subject to promising applications also outside of dermatology.

The lecture auditorium at the BfArM-building was almost taken to the last seat with more than 200 participants.

Professor Dr. med. Wolfram Sterry, acting president of the Deutsche Dermatologische Gesellschaft (German Dermatological Society) at the point in time of the 7th Annual Meeting of the GD informed about new therapy options by toll-like-receptor agonists.

Mechanism of Action of Fumar Acid Ester

Recent findings concerning an established therapy were introduced by professor Dr. med. Ulrich Mrowietz, Kiel. He reported about the mechanism of action of fumar acid esters which are applied in the systemic therapy of psoriasis. The product in tablet form licensed in Germany contains a defined compound of different fumar acid ester with dimethyl fumarate (DMF) as main compound.

The DMF-metabolite methylhy-drug fumarate (MHF) modifies the cytokine secretion of lymphocytes. The multiple effects finally jointly inhibit the translocation of the transcription factor NF?B which is indispensable for the survival of the immuno-regulating cells. The number of leukocytes decreases under therapy, however surprisingly the susceptibility for infects is not increased. The satisfactory long-term safety is considered to be an additional avail of the therapy. So far there is no indication concerning malignant tumors.

Possibly the indication spectrum of the fumar acid ester will have to be extended to other Th1-related diseases in the future. As DMF is obviously not directly involved in the effect, efforts are undertaken to develop a systemical MHF-mono preparation.

Immuno-modulatory Dermatotheraphy

“New therapeutic strategies can be deduced from recent findings regarding immunological causes of various dermatological diseases at present and in future”, explained professor Dr. med. Thomas Luger, Münster. In this context new inflammation inhibitors, immuno-modulators, the so-called "biologicals" and the cell therapy are to be differentiated.

To the inflammation inhibitors and immuno-modulators belong besides the TLR-agonists and the fumar acid esters (see above) also purine- and pyrimidine-synthesis inhibitors as well as calcineurin-inhibitors respectively immuno-modulators as Tacrolimus and Pimecrolimus. The latter are, as is generally known, authorized for the topical therapy of neurodermatitis und entail satisfactory results due to their good dermal tolerability. As first clinical studies have shown, Pimecrolimus is also systemically effective with psoriasis and atopical dermatitis.

Recombined proteins as interleucines, interferones, monoclonal antibodies and fusion proteins are summarized under the term "Biologicals". They are to control the function of the antigen-presenting cells, the T-cell-activation, the leukocyte-adhesion or the production of cytokines and chemokines. Some of these molecules have proven very effective for the treatment of inflammatory skin diseases (psoriasis) or skin tumors (T-cell-lymphoma).

Future prospects for the treatment of melanomae represent immunisation strategies on the basis of dendritic cells loaded with tumor antigens. The value of different DNA-based vaccines is at present analysed in clinical studies.

Professor Dr. med. Luger, the acting secretary general of the Deutsche Dermatologische Gesellschaft (German Dermatological Society) summarized the present and future treatment potential of immuno-related dermatoses.

Anti-apoptotic Effect of Vitamin D3

Dr. Burkhard Kleuser, Berlin expounded the reason why vitamin D3 has an apoptic effect in human keratinocytes. The active metabolite of vitamin D3, 1?,25-dihydroxy vitamin D3 probably develops its effect in the treatment of psoriasis via the formation of ceramides. As ceramides further apoptosis, the apoptosis level should actually increase under the influence of vitamin D3, however the contrary can be observed. Apparently vitamin D3 takes an anti-apoptotic effect.

The reason is, according to Kleuser the further metabolization of the ceramides which are transformed, influenced by vitamin D3, to anti-apoptic effective sphingosin-1-phosphate. At inhibiting of the formation of sphinghosin-1-phosphate by an inhibitor, (N,N-dimethylsphin-gosin), the anti-apoptotic effects of vitamin D3 are completely offset.

Enyzmes for the Repair of
UV-related Skin Damage

Professor Dr. med. Jean Krutmann, Düsseldorf, prize winner of the Dermopharmacy-Innovation Prize (DIP) conferred for the first time, informed about skin damage by UV-radiation and prospects for its repair. UVA- and UVB-radiation may entail among other effects pre-canceroses, epithelioma, basaloma, which are almost exclusively conveyed by DNS-damage. Through UV-light pyrimidine bases connect in the DNS-cords to cyclo butane pyrimidine dimers.

The physiological repair of these damages is very complex and can for example be facilitated by the enzyme endonuclease V which is not developed in humans. The exterior application of this enzyme, available in the form of a liposomal preparation, the immuno-suppressive effects of the UVB-radiation can reduced. The incidence of skin cancer in mice could be decreased dose-dependent after UV-radiation. Also with patients suffering from xeroderma pigmentosum who have disease-related an approximately 1000 times higher skin cancer risk, the frequency of actinic keratoses and basalioma decreased significantly.

In the future the topical application of DNS-repair enzymes could develop in particular in combination with the TLR-agonists and COX-inhibitors to a promising preventive concept for UV-related skin damages.

GD-member professor Dr. med. Dr. h. c. Thomas Ruzicka (right) director at the Hautklinik (Dermatological Clinic) at Heinrich-Heine-University was not only scientific conference head of the 7th Annual Meeting of the GD but he also engaged an excellent young pianist for the opening of the symposium "Topical immuno-modulators" in the guesthouse Petersberg.

Tolerability Tests without Animal Experiments

Professor Dr. med. Horst Spielmann, Bundesinstitut für Risikobewertung (Federal Institute for Risk Assessment), Berlin, reported about the validation of in-vitro methods as replacement of animal experiments. Animal experiments are on one hand stipulated by authorities as they serve the protection of staff and consumers when dealing with diverse substances and have been for a long time established and reliable for the assessment of detrimental properties. On the other hand, the animal welfare calls for a replacement of these tests.

Since 1986 an EU-guideline determines that animal experiments are impermissible as soon as a validated alternative method is available. Animal experiments for tests of cosmetic ready-to-use products have been prohibited in Germany since 1987 and starting 2003 in the entire EU. The question, however, remains unanswered whether the 7th amendment of the EU-cosmetic guideline adopted in February 2003 will be totally realizable, according to which no animal experiments will be permissible also for new cosmetic raw materials in ten years.

Meanwhile, there are examples on hand that safety-toxicological animal experiments can be replaced by animal-experiment free methods. These tests have to be sufficiently experimentally validated to prove their reproducibility and reliability. After successful validation, the OECD has in the meantime recognized certain in-vitro-tests for testing of the photo toxicity, the caustic effect on skin, the skin penetration, skin sensitization and embryo toxicity. Validated alternative methods for tests of the eye irritation are to be developed until 2006.

Activation of Endogenous Urea Synthesis

Private lecturer Dr. med. Johannes Wohlrab, Halle/Saale, explained how the urea synthesis can be stimulated. in keratinocytes This synthesis is reduced at atopical dermatitis, psoriasis and other skin diseases. An exogenous urea substitution increases on the one hand the water-binding capacity and the hydratation of the stratum corneum, however these effects are only of such a short duration that an application of several times a day is required. This is why the therapy concept aims at a stimulation of the endogenous urea production with the objective of obtaining an effect of longer durability.

Horny Layer Hydratation and UV-sensitivity

The question whether hydratation-enhancing preparations for topical application intensify the UV-sensitivity of the skin could not be finally answered to date. Studies in which the influence of such preparations for topical application on the efficiency of UV-radiation in the psoriasis therapy has been investigated had contradictory results. Open is still the question whether the UV-conditioned skin ageing is accelerated by a skin hydratation.

For the clarification of this question, a pilot study has been performed in the working group of professor Dr. med. Martina Kerscher, Hamburg. The results of this study were presented by Dr. med. Tilmann Reuther. In this study at ten testees with healthy skin, the influence of the ointment base Unguentum emulsificans with varying water content was tested on the UVB-sensitivity of the skin. There were neither sum score significant distinctions compared with the untreated control for the read-off medium minimal erythema dose (MED) nor for the erythema.

Thus, from the results of this study, it can be concluded that there is an increased UVB-sensitivity of the skin after application of hydratation-enhancing preparations for topical application. The universal validity of these findings has however be tested in further investigations with other bases and higher numbers of testees.

Private lecturer Dr. med. Johannes Wohlrab, scientific head of the 8th Annual Meeting of the GD on 30 in Halle/Salle and 31 March 2004, introduced possibilities for the activation of the keratinocyte urea synthesis.

Dermatotherapy at the Turning Point

In his concluding closing words of the 7th Annual Meeting of the GD, the vice-president of the GD, professor Dr. med. Hans Christian Korting, Munich, stated that the treatment of skin diseases is apparently at a turning point. Whereas many innovative concepts as biologicals, gene therapeutics and new complex active substance vehicles have been subject to controversial discussion for a long time, they are at present on the verge of being introduced in the market.

Unfortunately, the development chain of such pharmaceuticals only takes place to a minor extent in Germany. The necessary structures have been largely lost in the course of the last twenty years. New dermatological active substances are nowadays predominantly developed in the USA and in Japan, partly also in Switzerland and Austria, but no longer in Germany.

Summaries of all lectures held at the 7th Annual Meeting of the GD can be retrieved at the GD-homepage

From Molecule to Authorization

The GD-department Dermatopharmacology presented itself at the 7th Annual Meeting of the GD in a symposium under the title "From molecule to authorization" which comprised subjects along the entire pharmaceutical development- and value-added chain new dermatics have to pass.

With the example of the wound healing Dr. Andreas Goppelt, Neuried, explained how the progress achieved in gene technology can be made use of when searching for new dermatological active substances. In the course of the wound-healing process, hundreds of genes become active, which comply to 85 percent between men and mice. By comparing the gene-activation profiles at tissue tests of skin-healthy testees and diseased persons with chronical wounds, the genes relevant for wound healing can be identified which are then to be transferred genetically and applied for the furtherance of wound healing.

Professor Dr. Gregor Cevc, Munich, illustrated the concept of the so-called Transfersomen®. They are innovative carriers for topically applied active substances and adapt their form to the surroundings thus allowing a better transport of drugs into the skin as vehicle systems with fixed structures. As in-vitro tests with the glucocorticoid Triam cinolone acetonide could show, the same clinical effect could be achieved with a tenth part of the dose as with the conventional preparation. So far the concept has merely reached clinical tests of phase II.

By the permanent trend towards more systemically effective substances in dermatology, the requirement of effective clinical test strategies is rising. In order to keep the efforts in terms of time and costs in reasonable limits for the authorization of such dermatics, a concept of flexible clinical studies is favorable, according to Dr. Dr. Wolfgang Greb, Neuss. This concept is based on several interim analyses planned in advance the results of which determine the further study program according to a fixed plan set up before. Provided a good planning, one single study could be sufficient to obtain an authorization. The approving authorities principally show a positive attitude towards these concepts.


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